The present invention generally relates to benzothiazole compounds useful as adenosine receptor ligands. Specifically, the present invention relates to compounds having good affinity to the A2A-receptor and a high selectivity to the A1- and A3 receptors.
Adenosine modulates a wide range of physiological functions by interacting with specific cell surface receptors. The potential of adenosine receptors as drug targets was first reviewed in 1982. Adenosine is related both structurally and metabolically to the bioactive nucleotides adenosine triphosphate (ATP), adenosine diphosphate (ADP), adenosine monophosphate (AMP) and cyclic adenosine monophosphate (cAMP); to the biochemical methylating agent S-adenosyl-L-methione (SAM); and structurally to the coenzymes NAD, FAD and coenzym A; and to RNA. Together adenosine and these related compounds are important in the regulation of many aspects of cellular metabolism and in the modulation of different central nervous system activities.
The receptores for adenosine have been classified as A1, A2A, A2B and A3 receptors, belonging to the family of G protein-coupled receptors. Activation of adenosine receptors by adenosine initiates signal transduction mechanism. These mechanisms are dependent on the receptor associated G protein. Each of the adenosine receptor subtyps has been classically characterised by the adenylate cyclase effector system, which utilises cAMP as a second messenger. The A1 and A3 receptors, coupled with Gi proteins inhibit adenylate cyclase, leading to a decrease in cellular cAMP levels, while A2A and A2B receptors couple to Gs proteins and activate adenylate cyclase, leading to an increase in cellular cAMP levels. It is known that the A1 receptor system include the activation of phospholipase C and modulation of both potassium and calcium ion channels. The A3 subtype, in addition to its association with adenylate cyclase, also stimulates phospholipase C and so activates calcium ion channels.
The A1 receptor (326-328 amino acids) was cloned from various species (canine, human, rat, dog, chick, bovine, guinea-pig) with 90-95% sequence identify among the mammalian species. The A2A receptor (409-412 amino acids) was cloned from canine, rat, human, guinea pig and mouse. The A2B receptor (332 amino acids) was cloned from human and mouse with 45% homology of human A2B with human A1 and A2A receptors. The A3 receptor (317-320 amino acids) was cloned from human, rat, dog, rabbit and sheep.
The A1 and A2A receptor subtypes are proposed to play complementary roles in adenosine""s regulation of the energy supply. Adenosine, which is a metabolic product of ATP, diffuses from the cell and acts locally to activate adenosine receptors to decrease the oxygen demand (A1) or increase the oxygen supply (A2A) and so reinstate the balance of energy supply: demand within the tissue. The actions of both subtyps is to increase the amount of available oxygen to tissue and to protect cells against damage caused by a short term imbalance of oxygen. One of the important functions of endogenous adenosine is preventing damage during traumas such as hypoxia, ischaemia, hypotension and seizure activity.
Furthermore, it is known that the binding of the adenosine receptor agonist to mast cells expressing the rat A3 receptor resulted in increased inositol triphosphate and intracellular calcium concentrations, which potentiated antigen induced secretion of inflammatory mediators. Therefore, the A3 receptor plays a role in mediating asthmatic attacks and other allergic responses.
Adenosine is a neuromodulator, able to modulate many aspects of physiological brain function. Endogenous adenosine, a central link between energy metabolism and neuronal activity, varies according to behavioural state and (patho)physiological conditions. Under conditions of increased demand and decreased availability of energy (such as hypoxia, hypoglycemia, and/or excessive neuronal activity), adenosine provides a powerful protective fedback mechanism. Interacting with adenosine receptors represents a promising target for therapeutic intervention in a number of neurological and psychiatric diseases such as epilepsy, sleep, movement disorders (Parkinson or Huntington""s disease), Alzheimer""s disease, depression, schizophrenia, or addiction An increase in neurotransmitter release follows traumas such as hypoxia, ischaemia and seizures. These neurotransmitters are ultimately responsible for neural degeneration and neural death, which causes brain damage or death of the individual. The adenosine A1 agonists which mimic the central inhibitory effects of adenosine may therefore be useful as neuroprotective agents. Adenosine has been proposed as an endogenous anticonvulsant agent, inhibiting glutamate release from excitory neurons and inhibiting neuronal firing. Adenosine agonists therefore may be used as antiepileptic agents. Adenosine antagonists stimulate the activity of the CNS and have proven to be effective as cognition enhancers. Selective A2a antagonists have therapeutic potential in the treatment of various forms of dementia, for example in Alzheimer""s disease, and of neurodegenerative disorders, e.g. stroke. Adenosine A2a receptor antagonists modulate the activity of striatal GABAergic neurons and regulate smooth and well-coordinated movements, thus offering a potential therapy for Parkinsonian symptoms. Adenosine is also implicated in a number of physiological processes involved in sedation, hypnosis, schizophrenia, anxiety, pain, respiration, depression, and drug addiction (amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids). Drugs acting at adenosine receptors therefore have therapeutic potential as sedatives, muscle relaxants, antipsychotics, anxiolytics, analgesics, respiratory stimulants, antidepressants, and to treat drug abuse. They may also be used in the treatment of ADHD (attention deficit hyper-activity disorder).
An important role for adenosine in the cardiovascular system is as a cardioprotective agent. Levels of endogenous adenosine increase in response to ischaemia and hypoxia, and protect cardiac tissue during and after trauma (preconditioning). By acting at the A1 receptor, adenosine A1 agonists may protect against the injury caused by myocardial ischemia and reperfusion. The modulating influence of A2a receptors on adrenergic function may have implications for a variety of disorders such as coronary artery disease and heart failure. A2a antagonists may be of therapeutic benefit in situations in which an enhanced antiadrenergic response is desirable, such as during acute myocardial ischemia. Selective antagonists at A2a receptors may also enhance the effectiveness of adenosine in terminating supraventricula arrhytmias.
Adenosine modulates many aspects of renal function, including renin release, glomerular filtration rate and renal blood flow. Compounds which antagonise the renal affects of adenosine have potential as renal protective agents. Furthermore, adenosine A3 and/or A2B antagonists may be useful in the treatment of asthma and other allergic responses or and in the treatment of diabetes mellitus and obesity.
Numerous documents describe the current knowledge on adenosine receptors, for example the following publications:
Bioorganic and Medicinal Chemistry, 6, (1998), 619-641,
Bioorganic and Medicinal Chemistry, 6, (1998), 707-719,
J. Med. Chem., (1998), 41, 2835-2845,
J. Med. Chem., (1998), 41, 3186-3201,
J. Med. Chem., (1998), 41, 2126-2133,
J. Med. Chem., (1999), 42, 706-721,
J. Med. Chem., (1996), 39, 1164-1171,
Arch. Pharm. Med. Chem., 332, 39-41, (1999),
Am. J. Physiol., 276, H1113-1116, (1999) or
Naunyn Schmied, Arch. Pharmacol. 362, 375-381, (2000).
The present invention relates to compounds of the formula 
wherein R1 and R2 are as defined herewithin.
The present invention relates to the compounds of formula I per se, the use of compounds of formula I and their pharmaceutically acceptable salts for the manufacture of medicaments for the treatment of diseases related to the adenosine A2 receptor. The present invention further relates to the manufacture of compounds of formula I, medicaments based on these compounds and their production. The present invention also relates to the use of compounds of formula I in the control or prevention of illnesses based on the modulation of the adenosine system, such as Alzheimer""s disease, Parkinson""s disease, Huntington""s disease, neuroprotection, schizophrenia, anxiety, pain, respiration deficits, depression, drug addiction, such as amphetamine, cocaine, opioids, ethanol, nicotine, cannabinoids, or against asthma, allergic responses, hypoxia, ischaemia, seizure and substance abuse. Furthermore, compounds of the present invention maybe useful as sedatives, muscle relaxants, antipsychotics, antiepileptics, anticonvulsants and cardiaprotective agents for disorders such as coronary artery disease and heart failure. The most preferred indications in accordance with the present invention are those, which base on the A2A receptor antagonistic activity and which include disorders of the central nervous system, for example the treatment or prevention of Alzheimer""s disease, certain depressive disorders, drug addiction, neuroprotection and Parkinson""s disease as well as ADHD.
The present invention relates to compounds of the formula 
wherein
R1 is 3,6-dihydro-2H-pyran-4-yl, 5,6-dihydro-4H-pyran-3-yl, 5,6-dihydro-4H-pyran-2-yl, tetrahydropyran-2,3 or 4-yl, cyclohex-1-enyl, cyclohexyl, substituted or unsubstituted 1,2,3,6-tetrahydro-pyridin-4-yl or substituted or unsubstituted piperidin-4-yl, wherein when R1 is substituted, the substituent is xe2x80x94C(O)CH3 or xe2x80x94C(O)OCH3 in the 1-position of the N-atom;
R2 is lower alkyl, piperidin-1-yl, piperidin-1-yl substituted by hydroxy, phenyl, phenyl substituted by at least one group selected from the group consisting of xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x2)xe2x80x94C(O)xe2x80x94(CH2)nxe2x80x94NRxe2x80x22, xe2x80x94(CH2)n-halogen, lower alkyl and xe2x80x94(CH2)nxe2x80x94N(Rxe2x80x2)xe2x80x94(CH2)nxe2x80x94O-lower alkyl, morpholinyl, pyridinyl, pyridinyl substituted by at least one group selected from the group consisting of halogen, xe2x80x94N(Rxe2x80x2)xe2x80x94(CH2)nxe2x80x94Oxe2x80x94lower alkyl, lower alkyl, lower alkoxy, morpholinyl and xe2x80x94(CH2)n-pyrrolidinyl;
n is 0, 1 or 2;
Rxe2x80x2 is hydrogen or lower alkyl;
and pharmaceutically acceptable acid addition salts thereof.
As used herein, the term xe2x80x9clower alkylxe2x80x9d denotes a saturated straight- or branched-chain alkyl group containing from 1 to 6 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, n-butyl, i-butyl, 2-butyl, t-butyl and the like. Preferred lower alkyl groups are groups with 1-4 carbon atoms.
The term xe2x80x9chalogenxe2x80x9d denotes chlorine, iodine, fluorine and bromine.
The term xe2x80x9clower alkoxyxe2x80x9d denotes a group wherein the alkyl residues is as defined above, and which is attached via an oxygen atom.
The term xe2x80x9cpharmaceutically acceptable acid addition saltsxe2x80x9d embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
Preferred compounds of the present application are compounds of formula I, wherein R1 is 3,6-dihydro-2H-pyran-4-yl, for example the following compound:
[7-(3,6-dihydro-2H-pyran-4-yl)-4-methoxy-benzothiazol-2-yl]-carbamic acid methyl ester.
Further preferred are compounds, wherein R1 is tetrahydropyran-4-yl, for example the following compounds:
4-fluoro-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-benzamide,
N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-6-methyl-nicotinamide,
2-methoxy-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide,
2-ethoxy-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide,
2-ethyl-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide
N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-2-propyl-isonicotinamide,
2-isopropoxy-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide,
2-isopropyl-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide,
N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-2-pyrrolidin-1-ylmethyl-isonicotinamide,
morpholine-4-carboxylic acid [4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-amide,
4-hydroxy-piperidine-1-carboxylic acid [4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-amide,
2-(2-methoxy-ethylamino)-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide or
2-[(2-methoxy-ethyl)-methyl-amino]-N-[4-methoxy-7-(tetrahydro-pyran-4-yl)-benzothiazol-2-yl]-isonicotinamide.
Further preferred are compounds, wherein R1 is tetrahydropyran-2-yl, for example the following compounds:
2-bromo-N-[4-methoxy-7-(tetrahydro-pyran-2-yl)-benzothiazol-2-yl]-isonicotinamide,
4-fluoro-N-[4-methoxy-7-(tetrahydro-pyran-2-yl)-benzothiazol-2-yl]-benzamide,
N-[4-methoxy-7-(tetrahydro-pyran-2-yl)-benzothiazol-2-yl]-2-methyl-isonicotinamide or
N-[4-methoxy-7-(tetrahydro-pyran-2-yl)-benzothiazol-2-yl]-2-morpholin-4-yl-isonicotinamide
A further preferred group of compounds are those, wherein R1 is 1,2,3,6-tetrahydro-pyridin-4-yl, substituted by xe2x80x94C(O)CH3, for example the following compound:
N-[7-(1-acetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-4-methoxy-benzothiazol-2-yl]-4-fluoro-benzamide.
Preferred compounds of the present application are compounds of formula I, wherein R1 is piperidin-4-yl, substituted on the N-atom by xe2x80x94C(O)CH3, for example the following compounds:
N-[7-(1-acetyl-piperidin-4-yl)-4-methoxy-benzothiazol-2-yl]-4-fluoro-benzamide, morpholine-4-carboxylic acid [7-(1-acetyl-piperidin-4-yl)-4-methoxy-benzothiazol-2-yl]-amide,
N-[7-(1-acetyl-piperidin-4-yl)-4-methoxy-benzothiazol-2-yl]-2-methyl-isonicotinamide,
N-[7-(1-acetyl-piperidin-4-yl)-4-methoxy-benzothiazol-2-yl]-4-{[(2-methoxy-ethyl)-methyl-amino-}-benzamide,
N-[7-(1-acetyl-piperidin-4-yl)-4-methoxy-benzothiazol-2-yl]-4-methyl-benzamide,
N-[7-(1-acetyl-piperidin-4-yl)-4-methoxy-benzothiazol-2-yl]-2-morpholin-4-yl-isonicotinamide or
N-[7-(1-acetyl-piperidin-4-yl)-4-methoxy-benzothiazol-2-yl]-2-methoxy-isonicotinamide.
A preferred group of compounds of formula I are further those, wherein R1 is cyclohex-1-enyl, for example the following compound
(7-cyclohex-1-enyl-4-methoxy-benzothiazol-2-yl)-carbamic acid methyl ester.
Preferred compounds of the present application are compounds of formula I, wherein R1 is cyclohexyl, for example the following compounds:
N-(7-cyclohexyl-4-methoxy-benzothiazol-2-yl)-4-fluoro-benzamide,
N-(7-cyclohexyl-4-methoxy-benzothiazol-2-yl)-4-{[(2-methoxy-ethyl)-methyl-amino]-methyl}-benzamide or
N-(7-cyclohexyl-4-methoxy-benzothiazol-2-yl)-2-pyrrolidin-1-yl-methyl-isonicotinamide.
The present compounds of formula I and their pharmaceutically acceptable salts can be prepared by methods known in the art, for example, by processes described below, which process comprises
a) reacting a compound of formula 
xe2x80x83with a compound of formula 
xe2x80x83or with a compound of formula 
xe2x80x83to a compound of formula 
xe2x80x83wherein R1 and R2 are as defined above, or
b) hydrogenating a compound of formula 
xe2x80x83to a compound of formula 
xe2x80x83wherein X is a ring atom, selected from the group, consisting of O, N or C, which may be in different ring positions, and wherein the ring N atom may be substituted by xe2x80x94C(O)CH3 or xe2x80x94C(O)OCH3, or
c) reacting a compound of formula 
xe2x80x83with Ac2O
to a compound of formula 
xe2x80x83wherein the dotted line may be a bond and R2 is as described above, and if desired, converting the compounds obtained into pharmaceutically acceptable acid addition salts.
The compounds of formula I may be prepared in accordance with process variants a) to c) and with the following schemes 1 to 5. 
wherein R1xe2x80x2 is is 3,6-dihydro-2H-pyran-4-yl, 5,6-dihydro-4H-pyran-3-yl, 5,6-dihydro-4H-pyran-2-yl, cyclohex-1-enyl, or 1,2,3,6-tetrahydro-pyridin-4-yl and and Rxe2x80x3 is tetrahydropyran-2,3 or 4-yl, cyclohexyl or piperidin-4-yl;
Preparation of Compounds of Formula (4)
The starting 7-iodo-benzothiazole derivatives of formula (1) maybe prepared according to methods disclosed in EP 00113219.0. The starting tributylstannane compounds of formula (2) maybe obtained commercially, for example from Fluka, or may be prepared according to methods well known in the art.
The 7-iodo-benzothiazole derivative of formula (1) is reacted with an excess of a tributylstannane compound of formula (2) in an organic solvent, preferably dioxane, containing a palladium catalyst, preferably bis(dibenzylideneacetone)palladium(0), and a catalytic amount of a phosphine ligand, preferably trifurylphosphine. The reaction is carried out at elevated temperature, preferably about 100xc2x0 C., for about 2-24 hours, preferably about 16 hours. The product of formula (4) is isolated by conventional means, and preferably purified by means of chromatography or recrystallization.
Alternative Preparation of Compounds of Formula (4)
The starting boronic acid compounds of formula (3) may be obtained commercially, for example from Fluka, or may be prepared according to methods well known in the art.
The compounds of formula (4) may alternatively be prepared by treating 7-iodo-benzothiazole derivatives of formula (1) with an excess of a boronic acid compound of formula (3). The reaction is carried out in an aqueous solvent, preferably a mixture of water and dioxane, containing a palladium catalyst, preferably bis(dibenzylideneacetone)-palladium(0), and a catalytic amount of a phosphine ligand, preferably trifurylphosphine., and an inorganic base, preferably sodium carbonate. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 2-24 hours, preferably about 16 hours. The product of formula (4) is isolated by conventional means, and preferably purified by means of chromatography or recrystallization.
Preparation of Compounds of Formula (5)
Compounds of formula (5) may be prepared by hydrogenation of compounds of formula (4) in the presence of a hydrogenation catalyst, preferably 10% palladium on charcoal. These reactions maybe carried out in a variety of organic solvents, such as methanol, ethanol, or tetrahydrofuran, preferably methanol, at room temperature and at a pressure of one atmosphere or above, preferably at one atmosphere, for 16-72 hours, preferably about 72 hours. The product of formula (5) is isolated by conventional means, and preferably purified by means of chromatography or recrystallization.
Preparation of Compounds of Formula (6-1) or (6-2)
One method of preparation of compounds of formula (6-1) or (6-2) is by treatment of a compound of formula (4) or (5) with an excess of sodium hydroxide or potassium hydroxide in an aqueous solvent, preferably aqueous ethylene glycol. The reaction is carried out at elevated temperature, preferably about 100xc2x0 C., for about 1-16 hours, preferably about 3 hours. The product of formula (6-1) or (6-2) is isolated by conventional means, and preferably purified by means of chromatography or recrystallization.
Preparation of Compounds of Formula I-1 or I-2
One method of preparation of compounds of formula 1 or I-2 is by treatment of a compound of formula (6-1) or (6-2) with a slight excess of an appropriate acyl chloride of formula (7), which may be commercially available or may be prepared by methods well known in the art. The reaction is carried out in a non-protic organic solvent, preferably a mixture of dichloromethane and tetrahydrofuran, containing a base, preferably N-ethyldiisopropylamine or triethylamine, at room temperature for 2-24 hours, preferably 24 hours. The product of formula I is isolated by conventional means, and preferably purified by means of chromatography or recrystallization.
Alternative Preparation of Compounds of formula 1 or I-2
An alternative method of preparation of compounds of formula I involves treatment of an appropriate carboxylic acid of formula (8) with a stoichiometric equivalent of a peptide-coupling reagent, preferably O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate (HATU), in an ethereal solvent, preferably tetrahydrofuran, containing a base, preferably N-ethyldiisopropylamine, at room temperature for 30-90 minutes, preferably 1 hour. This mixture is then treated with a compound of formula (6) in a solvent mixture, preferably a mixture of tetrahydrofuran, dioxane and N,N-dimethylformamide, at room temperature for 16-24 hours, preferably 16 hours. The product of Formula I is isolated by conventional means, and preferably purified by means of chromatography or recrystallization.
Alternative Preparation of Compounds of Formula (6-2)
An alternative method of preparation of compounds of formula (6-2) is from intermediates of formula (13), the preparation of which is shown in reaction scheme 2 below. 
wherein R1xe2x80x2 and R1xe2x80x3 is as defined for scheme 1.
Preparation of Compounds of Formula (10)
The starting aryl bromide compounds of formula (9) may be obtained commercially, for example from Fluka, or may be prepared according to methods well known in the art. The starting tributylstannane compounds of formula (2) may be obtained commercially, for example from Fluka, or may be prepared according to methods well known in the art.
The aryl bromide compound of formula (9) is reacted with an excess of a tributylstannane compound of formula (2) in an organic solvent, preferably dioxane, containing a palladium catalyst, preferably bis(dibenzylideneacetone)palladium(0), and a catalytic amount of a phosphine ligand, preferably trifurylphosphine. The reaction is carried out at elevated temperature, preferably about 100xc2x0 C., for about 2-24 hours, preferably about 16 hours. The product of formula (10) is isolated by conventional means, and preferably purified by means of chromatography or recrystallization.
Alternative Preparation of Compounds of Formula (10)
The starting boronic acid compounds of formula (3) may be obtained commercially, for example from Fluka, or may be prepared according to methods well known in the art.
The compounds of formula (10) may alternatively be prepared by treating aryl bromide compounds of formula (9) with an excess of a boronic acid compound of formula (3). The reaction is carried out in an aqueous solvent, preferably a mixture of water and dioxane, containing a palladium catalyst, preferably bis(dibenzylideneacetone)-palladium(0), and a catalytic amount of a phosphine ligand, preferably trifurylphosphine., and an inorganic base, preferably sodium carbonate. The reaction is preferably carried out at the reflux temperature of the solvent, preferably about 100xc2x0 C., for about 2-24 hours, preferably about 16 hours. The product of formula (10) is isolated by conventional means, and preferably purified by means of chromatography or recrystallization.
Preparation of Compounds of Formula (11)
Compounds of formula (11) may be prepared by hydrogenation of compounds of formula (10) in the presence of a hydrogenation catalyst, preferably 10% palladium on charcoal. These reactions may be carried out in a variety of organic solvents, such as methanol, ethanol, tetrahydrofuran or dichloromethane, preferably a mixture of methanol and dichloromethane, at room temperature and at a pressure of one atmosphere or above, preferably at one atmosphere, for 0.5-16 hours, preferably about 1 hour. The product of formula (11) is isolated by conventional means, and preferably purified by means of chromatography or recrystallization.
Preparation of Compounds of Formula (12)
One method of preparation of compounds of formula (12) involves treatment of a compound of formula (11) with a slight excess of benzoyl isothiocyanate in acetone at a temperature between room temperature and reflux, preferably at room temperature, for 10-30 minutes, preferably 30 minutes. The product of formula (12) is isolated by conventional means, and preferably purified by means of chromatography or recrystallization.
Preparation of Compounds of Formula (13)
A compound of formula (12) is treated with a sub-stoichiometric amount of an alkali metal alcoholate in the corresponding alcohol solvent, preferably sodium methylate in methanol. The reaction is carried out at room temperature for about 0.5-2 hours, preferably about 1 hour. The product of formula (13) is isolated by conventional means, and preferably purified by means of chromatography or rerecrystallization.
Preparation of Compounds of Formula (6-2)
One method of preparation of compounds of formula (6-2) is by treatment of a compound of formula (13) with a stoichiometric equivalent of bromine in a halogenated organic solvent, preferably chloroform. The reaction is carried out at elevated temperature, preferably at the reflux temperature of the solvent, for about 12-18 hours, preferably about 16 hours. The product of formula (6) is isolated by conventional means, and preferably purified by means of chromatography or recrystallization.
Alternative Preparation of Compounds of Formula (10)
An alternative method of preparation of compounds of formula (10) is from an intermediate of formula (14), the preparation of which is shown in reaction scheme 3 below. 
where R1xe2x80x2 is as described in scheme 1.
Preparation of Compounds of Formula (14)
The aryl bromide compound of formula (9) is reacted with a slight excess of bis(pinacolato)diboron in an organic solvent, preferably dimethyl sulfoxide, containing a palladium catalyst, preferably dichloro(1,1xe2x80x2-bis(diphenylphosphino)ferrocene)-palladium(II) dichloromethane adduct, and an excess of potassium acetate. The reaction is carried out at elevated temperature) preferably about 80xc2x0 C., for about 2-24 hours, preferably about 2 hours. The product of formula (14) is isolated by conventional means, and preferably purified by means of chromatography or recrystallization.
Preparation of Compounds of Formula (10)
The starting vinyl bromide, vinyl iodide or vinyl triflate compounds of formula (15) may be obtained commercially, for example from Fluka, or may be prepared according to methods well known in the art.
One method of preparation of compounds of formula (10) is by treatment of a compound of formula (14) with a compound of formula (15) in the presence of a palladium catalyst, preferably dichloro(1,1xe2x80x2-bis(diphenylphosphino)ferrocene)-palladium(II) dichloromethane adduct, and an inorganic base, preferably sodium carbonate. The reaction is carried out in a mixture of solvents, preferably a mixture of ethanol, toluene and water. The reaction is carried out at elevated temperature, preferably about 80xc2x0 C., for about 0.1-2 hours, preferably about 20 minutes. The product of formula (10) is isolated by conventional means, and preferably purified by means of chromatography or recrystallization. 
wherein R2 is as described above. 
The preparation of compounds described in the above schemes is carried out in conventional manner.
The following abbreviations have been used:
HATU O-(7-azabenzotriazol-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluronium hexafluorophosphate
DMSO dimethyl sulfoxide
DMAP 4-dimethylaminopyridine
THF tetrahydrofuran
Isolation and Purification of the Compounds
Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography, thick-layer chromatography, preparative low or high-pressure liquid chromatography or a combination of these procedures. Specific illustrations of suitable separation and isolation procedures can be had by reference to the Preparations and Examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used.
Salts of Compounds of Formula I
The compounds of formula I may be basic, for example in cases where the residue R contains a basic group such as an aliphatic or aromatic amine moiety. In such cases the compounds of Formula I may be converted to a corresponding acid addition salt.
The conversion is accomplished by treatment with at least a stoichiometric amount of an appropriate acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. Typically, the free base is dissolved in an inert organic solvent such as diethyl ether, ethyl acetate, chloroform, ethanol or methanol and the like, and the acid added in a similar solvent. The temperature is maintained between 0xc2x0 C. and 50xc2x0 C. The resulting salt precipitates spontaneously or may be brought out of solution with a less polar solvent.
The acid addition salts of the basic compounds of Formula I may be converted to the corresponding free bases by treatment with at least a stoichiometric equivalent of a suitable base such as sodium or potassium hydroxide, potassium carbonate, sodium bicarbonate, ammonia, and the like.
The compounds of formula I and their pharmaceutically usable addition salts possess valuable pharmacological properties. Specifically, it has been found that the compounds of the present invention are adenosine receptor ligands and possess a high affinity towards the adenosine A2A receptor.
The compounds were investigated in accordance with the test given hereinafter.
The human adenosine A2A receptor was recombinantly expressed in chinese hamster ovary (CHO) cells using the semliki forest virus expression system. Cells were harvested, washed twice by centrifugation, homogenised and again washed by centrifugation. The final washed membrane pellet was suspended in a Tris (50 mM) buffer containing 120 mM NaCl, 5 mM KCl, 2 mM CaCl2 and 10 mM MgCl2 (pH 7.4) (buffer A). The [3H]-SCH-58261 (Dionisotti et al., 1997, Br J Pharmacol 121, 353; 1 nM) binding assay was carried out in 96-well plates in the presence of 2.5 xcexcg of membrane protein, 0.5 mg of Ysi-poly-1-lysine SPA beads and 0.1 U adenosine deaminase in a final volume of 200 xcexcl of buffer A. Non-specific binding was defined using xanthine amine congener (XAC; 2 xcexcM). Compounds were tested at 10 concentrations from 10 xcexcM-0.3 nM. All assays were conducted in duplicate and repeated at least two times. Assay plates were incubated for 1 hour at room temperature before centrifugation and then bound ligand determined using a Packard Topcount scintillation counter. IC50 values were calculated using a non-linear curve fitting program and Ki values calculated using the Cheng-Prussoff equation.
The preferred compounds show a pKi greater than 8.0.
The compounds of formula I and the pharmaceutically acceptable salts of the compounds of formula I can be used as medicaments, e.g. in the form of pharmaceutical preparations. The pharmaceutical preparations can be administered orally, e.g. in the form of tablets, coated tablets, dragees, hard and soft gelatine capsules, solutions, emulsions or suspensions. The administration can, however, also be effected rectally, e.g. in the form of suppositories, parenterally, e.g. in the form of injection solutions.
The compounds of formula I can be processed with pharmaceutically inert, inorganic or organic carriers for the production of pharmaceutical preparations. Lactose, corn starch or derivatives thereof, talc, stearic acids or its salts and the like can be used, for example, as such carriers for tablets, coated tablets, dragees and hard gelatine capsules. Suitable carriers for soft gelatine capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols and the like. Depending on the nature of the active substance no carriers are, however, usually required in the case of soft gelatine capsules. Suitable carriers for the production of solutions and syrups are, for example, water, polyols, glycerol, vegetable oil and the like. Suitable carriers for suppositories are, for example, natural or hardened oils, waxes, fats, semi-liquid or liquid polyols and the like.
The pharmaceutical preparations can, moreover, contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorants, salts for varying the osmotic pressure, buffers, masking agents or antioxidants. They can also contain still other therapeutically valuable substances.
Medicaments containing a compound of formula I or a pharmaceutically acceptable salt thereof and a therapeutically inert carrier are also an object of the present invention, as is a process for their production, which comprises bringing one or more compounds of formula I and/or pharmaceutically acceptable acid addition salts and, if desired, one or more other therapeutically valuable substances into a galenical administration form together with one or more therapeutically inert carriers.
In accordance with the invention compounds of formula I as well as their pharmaceutically acceptable salts are useful in the control or prevention of illnesses based on the adenosine receptor antagonistic activity, such as Alzheimer""s disease, Parkinson""s disease, neuroprotection, schizophrenia, anxiety, pain, respiration deficits, depression, asthma, allergic responses, hypoxia, ischaemia, seizure and substance abuse. Furthermore, compounds of the present invention may be useful as sedatives, muscle relaxants, antipsychotics, antiepileptics, anticonvulsants and cardiaprotective agents and for the production of corresponding medicaments.
The most preferred indications in accordance with the present invention are those, which include disorders of the central nervous system, for example the treatment or prevention of certain depressive disorders, neuroprotection and Parkinson""s disease.
The dosage can vary within wide limits and will, of course, have to be adjusted to the individual requirements in each particular case. In the case of oral administration the dosage for adults can vary from about 0.01 mg to about 1000 mg per day of a compound of formula I or of the corresponding amount of a pharmaceutically acceptable salt thereof. The daily dosage may be administered as single dose or in divided doses and, in addition, the upper limit can also be exceeded when this is found to be indicated.
Manufacturing Procedure
1. Mix items 1, 2, 3 and 4 and granulate with purified water.
2. Dry the granules at 50xc2x0 C.
3. Pass the granules through suitable milling equipment.
4. Add item 5 and mix for three minutes; compress on a suitable press.
Manufacturing Procedure
1. Mix items 1, 2 and 3 in a suitable mixer for 30 minutes.
2. Add items 4 and 5 and mix for 3 minutes.
3. Fill into a suitable capsule.
The following preparation and examples illustrate the invention but are not intended to limit its scope.